The epidermal growth factor receptor (EGFR) family comprises four closely related receptors including, for example, HER1/EGFR, HER2, HER3 and HER4 (“HER family members”) that are involved in cellular responses such as differentiation and proliferation. HER family members are typically involved in stimulating signaling pathways (e.g., PI3K signaling pathway) that promote multiple processes that are potentially cancer-promoting (e.g. proliferation, angiogenesis, cell motility and invasion, decreased apoptosis and induction of drug resistance). As such, over-expression of Her family members are frequently associated with many cancers including, for example, breast, lung, colorectal, ovarian, renal cell, bladder, head and neck cancers, glioblastomas, and astrocytomas.
Several Her family antagonists have been shown to offer clinical benefit for the treatment of cancer including, for example, erlotinib, gefitinib and lapatinib. Anti-EGFR antibodies have also shown clinical utility, including cetuximab and panitumamab which are approved for the treatment of EGFR-expressing, metastatic colorectal carcinoma. A breakthrough in the field of EGFR-targeted therapy occurred in 2004 with the identification of somatic mutations in the EGFR gene, which were closely associated with a favorable clinical response to gefitinib and erlotinib treatment in NSCLC patients. These genetic alterations consisted of small in-frame deletions or point mutations in EGFR exons 18-24, which encode the kinase domain of the protein and are clustered in two mutational ‘hot spots’ in the EGFR gene.
In addition to the EGFR family, the type 1 IGF receptor (IGF1R) has recently become a recognized target for the treatment of cancer. IGF1R is a transmembrane receptor tyrosine kinase (RTK) that is responsible for mediating IGF bioactivity. The IGF1R gene is located on chromosome 15q26 and encodes a single polypeptide of 1367 amino acids that is constitutively expressed in most cells. IGF1R is frequently overexpressed in tumours, including melanomas, cancers of the colon, pancreas, prostate and kidney. IGF1R activation may lead to autophosphorylation on tyrosines 1131, 1135 and 1136 in the kinase domain, followed by phosphorylation of juxtamembrane tyrosines and carboxy-terminal serines. IGF1R activation or overexpression is associated with an increased propensity for tumor cell invasion and metastasis. IGF1R activation also protects cells from a variety of apoptosis-inducing agents, including osmotic stress, hypoxia and anti-cancer drugs. IGF1R is also believed to suppress apoptosis primarily through the phosphoinositide 3-kinase (PI3K) pathway. Following phosphorylation of IRS-1 by the activated IGF1R, PI3K is activated by binding its regulatory subunit to IRS-1. This interaction leads to an increase in the levels of phosphatidylinositol 3,4,5-triphosphate (PIP3), which leads to recruitment and activation of phosphoinositide-dependent kinase-1 and AKT/protein kinase B. Given that IGF1R is an important target for cancer therapy, methods are needed to determine whether a subject will be responsive to treatment with an IGF1R inhibitor.